Para-alkenylphenoxy-hydroxy-isopropylaminopropane

ABSTRACT

PARA - ALKYL SUBSTITUTED PHENOXY - HYDROXY - ISOPROPYLAMNOPROPANE, ITS PREPARATION, PHARMACUTICAL COMPOSITION CONTAINING THIS COMPOUND, AND THE USE THEREOF IN THE TREATMENT OF CARDIAC AND VASCULAR DISEASE.

United States Patent Gee 3,531,108 Patented Dec. 28, 1971 U.S. Cl. 260-5703 1 Claim ABSTRACT OF THE DISCLOSURE Para allyl substituted phenoxy hydroxy isopropylaminopropane, its preparation, pharmaceutical compositions containing this compound, and the use thereof in the treatment of cardiac and vascular diseases.

This application is a division of applicants application Ser. No. 808,316, filed Mar. v18, 1969 and now U.S. Pat. No. 3,555,161.

This application is a continuation-in-part of our copending application Ser. No. 558,226 filed June 17, 1966, and now U.S. Pat. No. 3,466,376, which in turn is a continuation-in-part of our application Ser. No. 521,436 filed Jan. 18, 1966, and now U.S. Pat. No. 3,466,325.

The principal object of this invention is to provide a new alkenylphenoxy-hydroxyalkyl isopropylamine having valuable pharmacological properties.

It is still a further object of the invention to provide a new compound which can be formulated into pharmacological preparations in dosage units.

Another object of the invention is to provide a compound which may be employed in the treatment of cardiac and vascular diseases.

It is a still furthre object of the invention to provide a medicinal compound which can be used to protect a patients heart against excessive sympathetic stimulation.

It is a still further object of the invention to provide a new medicinal compound which can be used in the treatment of cardiac and vascular diseases to protect the patients heart against increased blood levels of epinephrine and norepinephrine.

A particular object of the invention is to provide a compound which has a much weaker blocking effect on the ,8-receptors of the bronchia and the smooth muscles of the blood vessels than on the ,B-receptors of the heart muscles. This means that the desired compound will have a more specific activity toward the heart, a property which in many cases is of significant importance in clinical use; for example, in treating patients who also have an asthmatic condition.

It is a further object of the invention to provide a novel compound for the treatment of cardio-vascular diseases which has local anesthetic effects.

These and other related objects are achieved by providing a new allylphenoxy-hydroxyalkyl isopropylamine characterized by the general formula:

( JHZ-CH=CH2 The allylphenoxy 2-hydroxy-3-isopropylaminopropane described above (sometimes referred to herein as the Para Isomer as distinguished from the Ortho Isomer in which the allyl group is in the ortho position) may be conveniently prepared by a process which comprises reacting an allylphenoxy-2,3-epoxypropane, which may be represented by the formula lilH -CH CH with a compound containing an active hydrogen atom and either an isopropylamino group or an atom or group of atoms which is capable of being converted into an isopropylamino group. These reactants may be characterized by the formula: HX, wherein X may be a halogen atom or an amino group such as isopropylamine. When X is an unsubstituted amino group, the resulting product can then be isopropylated by techniques which are well known; for example, by carrying out a reductive isopropylation in the presence of acetone and a reducing agent such as sodium borohydride, potassium borohydride, lithium aluminum hydride, and the like.

Since the new compound described above contains an asymmetric carbon atom, it exists in optically active forms which can be resolved into optical antipodes, the dexto and levo forms, by well known techniques employing e.g. optically active acids.

The allylphenyl-2,3-epoxypropyl ether described above may be prepared by reacting allylphenol with an epihalohydrin such as epichlorohydrin.

The allylphenoxy-isopropanolamine disclosed herein has been shown to possess valuable pharmacological properties. At relatively low dosage levels it has been found to block the effect of intravenously administered cardiac stimulants, such as isoprenaline, and the eliects of sympathetic stimulation of the heart and the fat tissue. It is, in particular, very useful in alleviating the effects of angina pectoris and in lowering blood pressure.

The acute and chronic toxicity of this compound is very low, and experiments show that it is well absorbed from the gastrointestinal tract and that its effect is of long duration. The compound may, therefore, be clinically used, in particular for the treatment of cardiac and vascular diseases under conditions such that the heart has to be protected against excessive sympathetic stimulation; e.g., during mental stress or muscular work, circumstances which are known to increase the level of the sympathomimetic amines epinephrine and norepinephrine in the blood. This is especially so in the case of patients also suffering from asthma, for other beta blocking drugs such as Inderal or Aptin (the ortho isomer of the compound disclosed herein) should not be administered to such patients. Furthermore, the substance has blood pressure lowering activity in patients suffering from hypertension.

The compound of the invention will normally be administered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable nontoxic, acid addition salt, e.g., the hydrochloride, lactate, acetate, sulfamate, and the like, in association with a pharmaceutically acceptable carrier. Accordingly, terms relating to the novel compound of this invention whether generically or specifically are intended to include both the free amine base and the acid addition salts of the free base, unless the context in which such terms are used, e.g., in the specific examples, would be inconsistent with the broad concept. The carrier may be a solid, semisolid or liquid diluent or an ingestible capsule. These pharmaceutical preparations constitute a further aspect of this invention. Usually the active substance will constitute between 0.1 and 95% by weight of the preparation, more specifically between 0.5 and 20% by weight for preparations intended for injection and between 2 and 50% by weight for preparations suitable for oral administration.

To produce pharmaceutical preparations containing a compound of the invention in the form of dosage units for oral application, the compound may be mixed with a solid pulverulent carrier, e.g., lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch, amylopectin, laminaria powder or citrus pulp powder, cellulose derivatives, or gelatin, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol waxes, and the like, and then compressed to form tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, e.g., gum arabic, gelatin, talcum, titanium dioxide, and the like. Alternatively, the tablet can be coated with a lacquer dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order readily to distinguish between tablets containing different active substances ordifferent amounts of the active compound.

For the preparation of soft gelatin capsules (pearlshaped closed capsules) consisting of gelatin and, e.g., glycerol, the active substance may be admixed with a vegetable oil. Hard gelatin capsules may contain granulates of the active substance in combination with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol, starches (e.g., potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage units for rectal application can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatin rectal capsules comprising the active substance in admixture with vegetable oil or parafiin oil.

Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing from about 0.2% to about 20% by weight of the active substance, herein described, the balance being sugar and a mixture of ethanol, water, glycerol, and propylene glycol. Optionally such liquid preparations may contain coloring agents, flavoring agents, saccharine and carboxymethylcellulose as a thickening agent.

Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from about 0.5% to about 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may convenientl be provided in various dosage unit ampules.

4 The following examples illustrate the principles and practice of the instant invention.

EXAMPLE 1 Epichlorohydrin (5.5 grams) was added to a solution containing 4 grams of p-allylphenol and 2 grams of sodium hydroxide in 25 milliliters of water. The resulting mixture was stirred overnight and the reaction product then extracted with ether. The ether solution was dried over magnesium sulphate and evaporated to provide 6.5 grams of a reaction product residue (p-allylepoxypropoxybenzene) which was used without further purification.

A mixture of 6.5 grams of isopropylamine, 6.5 grams of isopropanol, and 6.5 grams of the p-allylepoxypropoxybenzene was refluxed with continual stirring for about 4 hours. The isopropanol and unreacted isopropylamine were then removed by distillation. The resulting reaction product was dissolved in 2 M hydrochloric acid, and the solution was washed with ether. The acid solution was then made alkaline, and the amine thus liberated was extracted with ether. The ether solution was then dried over potassium carbonate and the excess solvent evaporated. The l-(p-allylphenoxy) 2 hydroxy-3-isopropylaminopropane was then recrystallized twice from petroleum ether (boiling range 40 C. to 60 C.) to provide 2.9 grams of a product having a melting point of 55 C.

The corresponding hydrochloride was prepared by dissolving 2 grams of the product, prepared above, in 20 milliliters of acetone, and adding to the resulting solution acetone saturated with hydrogen chloride until the pH was reduced to about 3. The precipitated hydrochloride salt was then recrystallized from acetone to yield 1.5 grams of a material having a melting point between 107 C. and 109 C.

The following examples illustrate the preparation of pharmaceutical formulations containing the active ingredients of this invention.

EXAMPLE 2 A syrup containing 2% (weight per volume) of the active substance was produced from the following ingredients:

l-(p allylphenoxy)-2-hydroxy-3-isopropylaminopropane HCl2.0 g.

Saccharin--0.6 g.

Sugar30.0 g.

Glycerol-5.0 g.

Flavoring agent-0.1 g.

Ethanol 96%10.0 ml.

Distilled water to 100.0 ml.

The sugar, saccharin and the ether salt were dissolved in 60 grams of hot water. After cooling, the glycerol and a solution of the flavoring agent in ethanol was added. The mixture was then made up to a volume of milliliters With water.

The active substances shown above may be replaced by other pharmaceutically acceptable acid addition salts.

EXAMPLE 3 Two hundred and fifty grams of 1-(p-allylphenoxy)- 2-hydroxy-3-isopropylaminopropane hydrochloride were mixed with 175.8 grams of lactose, 169.7 grams of potato starch and 32 grams of colloidal silica. The mixture was moistened with a 10% gelatin solution and granulated through a 12 mesh sieve. After drying, grams of potato starch, 50 grams of talc, 2.5 grams of magnesium stearate were mixed in and the resulting mixture was pressed into tablets (10,000) containing 25 milligrams of active substance which were suitable for use as tablets. The tablets were marked with break lines to enable a dose other than 25 milligrams or multiples thereof to be administered.

EXAMPLE 4 One gram of l-(p-allylphenoxy)-2-hydroxy-3-isopropylaminopropane hydrochloride, 0.8 gram of sodium chloride and 0.1 gram of ascorbic acid were dissolved in suffi- The results are presented in the following table.

TABLE 2.BLOCKADE OF THE EFFECT OF ISOPRENALINE ON CAT (DOSE GIVING 50% BLOCKADE OF CONTROL RESPONSE) cient distilled water to make 100 milliliters of solution. 5 Ortho isomer, Para isomer,

This solution, each milliliter of which contained millimgJkg' 1119/1111- grams of the active substance, was used to fill ampules Heartrate (positive chronotropic street)- 0.02 0. 06

which were sterilized by heating for minutes at 120 C. iggfig gggg g force 11mm 0 06 O 2 The allylphenoxy-propoxy-isopropanolamine described lglo d re sureo werihbhe 0.01 2.5

- er1p era vasou ar resistanoe. 0.04 3.6

herein, lncludmg the optical lsomers and racemic mixtures 10 Intrinsic flvreceptor stimulation, pep

thereof, has been shown to possess valuable pharmacocent of max. isoprenaline response-.- 24 29 logical properties. In low doses they block the eflfect of lntravenously adminlstered isoprenaline as well as the EXAMPLE 6 effects of sympathetic stlmulation on the heart, while at the same time having minimal effect on the bronchla and 15 Anesthetized cats the smooth muscles of the blood vessels.

In determining the approximate toxiclty in mice, male By this test an evaluation of the two drugs influence on mi e weighing -30 grams were u ed, The ni al were the pressor response to i.v. in ected adrenaline was made. observed for 72 hours. Comparisons made with the ortho The fi-receptor blocker was administered in increasing i m r are hown in the t ble, 20 amounts. Ten minutes after each dose adrenaline was injected in a dose that gave an increase in blood pressure Table Toxlclty In mouse amounting to about 30 mm. Hg in a control test. Table 3 I.p. administration: Mg./kg. shows the mean results obtained which indicate that the Para isomer 110 para isomer does not potentiate the pressor effect of adren- Ortho isomer 130 25 aline to the same degree as the ortho isomer does.

TABLE 3 Ortho isomer Para isomer Control Response RGSIJOHSB RESPONSE to adrenato adrenato adrena- Dose, rug/kg. line, mm. Maximal line,mm. Maximal line, mm. Maximal LV. Hg B.P.level Hg B.P.1evel Hg Bl. level 0 (control) 31 177 32 181 27 1s 64 208 184 27 1s 66 20s 42 183 28 1a 72 203 43 184 32 1s 80 202 185 32 15 91 194 so 187 as 15 90 183 64. 176 32 14 1 During adrenaline efiect, mm. Hg.

EXAMPLE 5 EXAMPLE 7 ,B-Blocking activity on anesthetized, reserpinized, Isolated spirally cut tracheal smooth muscle from vagotomized and adrenalectomized cat guinea pig The mean arterial blood pressure, heart rate, cardiac contractile force (by means of a strain gauge arch sutured to the right ventricle) and peripheral vascular resistance in a hind leg (perfusion pressure recorded under constant flow delivered by sigma motor pump) were recorded.

The p-blocking potency of the two drugs was determined by testing how increasing doses influenced responses to a dose of i.v. injected isoprenaline (pl-receptor stimulant). Potency comparisons were based on doses of the test substances (ortho and para isomers) giving 50% blockade of the effect of isoprenaline (ED Further the intrinsic p-stimulating doses were determined.

The procedure was as follows:

Cats weighing between 2.5 and 5.0 kg. were anesthetized with pentobarbital sodium (30 mg./kg. i.p.). The chest was opened and the lungs were artificially respirated. Laparatomy was performed and both adrenal glands were removed. Both vagal nerves were cut in the neck. Arterial blood pressure was recorded from a cannula in one carotid artery connected to a Statham transducer. Heart rate was recorded by a cardiotachometer triggered by the ECG of the animal. The recordings were made on an Ofiuer dynograph.

The animals were pretreated with reserpine (5 rug/kg. i.m.) about 18 hours before the experiment. This treatment probably produced practically complete depletion of myocardial catecholamines since repeated controls showed that the heart did not respond to strong electrical stimulation of the stellate ganglis nor did the heart contain any measurable amount of catecholamines.

Interaction of the para isomer and the ortho isomer with isoprenaline on the mortality of guinea pigs exposed to a histamine aerosol.

The method used was developed by Konzett & Rossler Arch. Exp. Pat. Pharmak. (1940), 71. The li-blocker to be tested was injected (s.c.) 15 minutes before exposure to histamine aerosol. Results are shown in Table 4.

TABLE 4 Isoprena- Mortality Antagonist line, 0.05 (dead/ dose, mg./kg. rug/kg. tested) None 8/8 Ortho 0.05 1/4 Ortho 0.1 2/8 Isoprenaline (a ,B-receptor stimulant and therefor bronchodilating agent) protects the animals against histamine-aerosol.

Both ,B-blockers counteract this effect of isoprenaline; the Para Isomer, however, at doses which are 40 times higher than the Ortho Isomer. Parameter: death of the animals in bronchoconstriction.

The conclusions to be drawn from the foregoing tests are that the para isomer is about 3 times weaker than the ortho isomer as regards cardiac fi-receptor blockade. The fi-blocking activity of the para isomer in vascular and tracheal smooth muscle was only to A of that of the ortho isomer. This indicates a clinical advantage for the para over the ortho isomer when the cardiac Li-blockade is utilized therapeutically, because the fi-blockade in smooth muscle may be disadvantageous.

The para isomer has an intrinsic cardiac stimulating action of the same order as the ortho isomer which may be of value when treating patients With latent cardiac failure.

With respect to dosages, clinical tests have shown as reported in the parent application, of which the present application is a continuation-in-part, that the ortho isomer may be administered orally in single or individual daily doses for a period of up to consecutive days. Four daily oral doses of 40 mg. have been used. For two patients a total dosage of 360 mg. was administered in three equal doses during one day. Five patients with minor cardiovascular disorders Were studied after a single oral dose of 40 mg. In another case oral doses were 10 to 40 mg. in divided doses. In still other tests, the ortho isomer was administered orally at a dose of 0.5 mg. per kg. of body weight (total dose 40 mg). In still other trials, work load tests were carried out one hour after oral administration of 0.75 mg. per kg. of body weight of the ortho isomer dissolved in water (total dose 60 mg.). In intravenous injections, the ortho isomer was administered in the dosage of 0.5 mg./kg. dissolved in 100 ml. of water. Two tablets containing mg. of the ortho isomer Were administered in a double blind test.

As noted, however, the para isomer has a weaker effect TABLE 5.EFFECTS OF POSITION ISOMERS OF THE ALLYL DERIVATIVES Blockade of isoprenaliuo response, ED o, mgjkg. Acute Positive toxicity Intrinsic chronotropic in mice, Qompound heart Blood and inotropic LD (isomer) stimulation 1 pressure response rngjkg.

Ortho ally] Very Weak. 0.01 0. 1 Meta allyl Weak 0.02 0. 2 Para ally1 Very weak 6 0. 5 150 1 Rabbit Langendorff heart. 2 Hexamethonium treated cat I.V. administration.

The claim is: 1. Para-allylphenoxy 2 hydroXy-3-isopropylaminopropane.

References Cited UNITED STATES PATENTS 9/1969 Brandstrom et al. 200l.l7 9/1969 Brandstrorn et al. 42433O ROBERT V. HINES, Primary Examiner US. Cl. X.R.

* $53 33". v UNITED STATES JPATENT OFFICE CERTIFICATE OF CORRECTION 3,631,108 Dated April 6, 1972 Patent No.

Inventoflg) Arne Elof Brandstrom et a1.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 2 line M, change "dexto" to dextro Col. 2 line 1 delete e.g.

Col. 5 line 75, change "ganglis" to ganglia Col. 6 line 32, change "16"00 165 Col. 6, line 33, Change "16" to 167 7 Col. 6 line 3 1,"ch'ange "16" to 162 001. 6 line '35, change "16" to 160 Col. 6 line 36, change "15" to 156 Col. 6 line 37, change "15" to '153 Col. 6 line 38, change "l t" to 1 16 Signed and sealed this 1 1 th day of July 1 972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents 

